The present invention relates to novel bis-platinum complexes and to pharmaceutical compositions containing them.
While cisplatin is widely used because of its antitumor activity, the search has continued for more powerful agents.
U.S. Pat. No. 4,225,529, discloses a cis coordinated compound of platinum having four ligands. (X, Y, A & B). The ligands X and Y are the same or different ligands selected from the group comprising a halide, sulphate, phosphate, nitrate, carboxylate, or substituted carboxylate and water. A and B are the same or different straight chain amines coordinated to the Pt through their N atoms, such that the platinum is represented by Pt.sup.2+. The "diaquo compound" is formed by a literature method described in the Indian Journal of Chemistry, 8, 143 (1970).
U.S. Pat. No. 4,250,189, discloses platinum coordinated compounds of Pt.sup.2+ or Pt.sup.4+. The Pt.sup.2+ compounds have four ligands, two of the ligands (X and Y) being selected from the group sulphate, phosphate, nitrate, carboxylate, or substituted carboxylate and water. The other two ligands are amines linked for example by an alkylene. The compound is contemplated for pharmaceutical use with a carrier.
U.S. Pat. No. 4,533,502, discloses platinum (II) compounds and their method of preparation. The starting compound is a cis - [PtL.sub.2 -I.sub.2 ] compound where L is an amine bonded to the Pt through the nitrogen and I is iodine. The starting compound is converted into cis-platinum (II) compounds similar to those in U.S. Pat. No. 4,225,529 above or a complex where two platinum (II) units are bridged by tetracarboxylate and each of the platinum (II) atoms are bonded to two of the carboxylate groups of the tetracarboxylate.
U.S. Pat. No. 4,565,884, describes a bis-platinum complex. The complex is linked by a central ligand with two pairs of acidic groups which could be carboxylates, sulphonates or phosphonates. The acids may be aromatic ring systems, alkyl cyclic ring systems or suitable aliphatic groups.
U.S. Pat. No. 4,571,335, discloses cis platinum (II) compounds that are usable for inhibiting herpes virus where the ligands include amines, dicarboxylic acids, and sulphonates.
The patents noted above discuss various Pt(II) and Pt (IV) compounds which have been found to have antitumor activity or pharmaceutical applications. The majority of these compounds are of the general formula cis-[PtLL'X.sub.2 ] or cis-[PtLL'(X.sub.2)(Y.sub.2)] for the Pt (II) and Pt(IV) forming complexes, respectively. L normally represents amine ligands where X is normally a halogen and Y is normally hydroxy. Those bis-platinum complexes prepared in the patents above were linked through carboxylate bridges. The carboxylate linkage merely serves as a temporary carrier vehicle. Upon administration in pharmaceutical applications, such complexes undergo rapid hydrolysis to produce two cis monoplatinum moieties which are delivered to the active site. There is no recognition in the art of a pharmaceutically active form of a bis-diplatinum complex which is delivered as an intact bis complex to the active site.
Accordingly, it is an object of this invention to produce a stable bis-platinum complex for antitumor and pharmaceutical applications, the complex being resistant to chemical breakdown prior to engaging in its pharmaceutical function.
It is a further object of the present invention to produce an improved coordinated platinum complex, the complex exhibiting increased tumor inhibition.
A still further object is to provide a bis-coordinated platinum complex capable of being formulated for use in pharmaceutical functions.